Portal hypertension

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Based on the etiology, portal hypertension may be classified as pre-hepatic, intra-hepatic, and post-hepatic. Intra-hepatic portal hypertension classified into pre-sinusoidal, sinusoidal, and post-sinusoidal disorders. Based on the function impairment in the liver, portal hypertension may be classified as cirrhotic and non-cirrhotic. The exact pathogenesis in portal hypertension is disturbance in normal physiology of portocaval circulation. The main factors that affect the pressure gradient in blood vessels are blood flow (Q) and vessel radius (r) in a direct and inverse way, respectively. Portal hypertension is related to elevation of portal vasculature resistance. Peripheral vasodilatation is the basis for decreased systemic vascular resistance and mean arterial pressure, plasma volume expansion, elevated splanchnic blood flow, and elevated cardiac index. Fourteen different genes are involved in the pathogenesis of portal hypertension. Homozygous missense mutation in DGUOK gene is found to be related with non-cirrhotic portal hypertension. On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension. The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome. Pharmacological medical therapy is recommended among patients with cirrhosis and portal hypertension which are without esophageal varices, with esophageal varices but not yet bleeding, with esophageal varices that is bleeding, and with esophageal varices that has already bled. Pharmacological medical therapies for portal hypertension include non-selective beta blockers (NSBB), analogues of nitric oxide (NO), and vasoactive agents. Surgery is not the first-line treatment option for patients with portal hypertension. Surgery is usually reserved for patients with either severe cirrhosis, esophageal varices, splenomegaly, ascites, or liver failure. There are no established measures for the primary prevention of portal hypertension. Effective measures for the primary prevention of liver diseases, as the main causes of portal hypertension, include hepatitis B vaccination, avoiding unprotected sex relations, precise screening of the blood products before infusion, alcohol consumption reduction, overweight and obesity prevention, and diabetes mellitus prevention. There are also no established measures for the secondary prevention of portal hypertension. Effective measures for the secondary prevention of liver diseases, as the main causes of portal hypertension, include treatment of hepatitis B and hepatitis C infections, alcohol abuse management, weight loss or management, and proper management of diabetes mellitus.

In 1511, Leonardo da Vinci, Italian Renaissance polymath, first describe the portal hypertension in an illustration in his textbook “De humanis corpore“. “… the artery and the vein which go from the spleen to the liver become so large, to block the blood coming from the mesenteric vein; the latter vein dilates and becomes tortuous like a snake, that the liver dries and become like frozen bran, in colour and consistency…”, this presentation was inaccurately described as the cause of portal hypertension. In 1937, William Thompson, a Canadian biologist, measured the portal vein pressure for the first time. He did the measurements in the open abdomen for both inferior vena cava (IVS) and portal vein. In 1939, Crafoord and Fenckner, Dutch cardiac surgeons, used sclerosing agents (quinine solutions) to treat the esophageal varices via endoscopy. The procedure was rarely used because of high rates of re-bleeding. In 1980s, researchers have observed that endoscopic sclerotherapy is more efficient than surgical shunting in preventing recurrent variceal bleeding. In 1967, Thomas Earl Starzl, an American physician, mentioned that liver transplantation is the only way to treat both portal hypertension and the underlying hepatic disease.

Based on the etiology, portal hypertension may be classified as pre-hepatic, intra-hepatic, and post-hepatic. Intra-hepatic portal hypertension classified into pre-sinusoidal, sinusoidal, and post-sinusoidal disorders. Based on the function impairment in the liver, portal hypertension may be classified as cirrhotic and non-cirrhotic.

The exact pathogenesis in portal hypertension is disturbance in normal physiology of portocaval circulation. The main factors that affect the pressure gradient in blood vessels are blood flow (Q) and vessel radius (r) in a direct and inverse way, respectively. Portal hypertension is related to elevation of portal vasculature resistance. Peripheral vasodilatation is the basis for decreased systemic vascular resistance and mean arterial pressure, plasma volume expansion, elevated splanchnic blood flow, and elevated cardiac index. Fourteen different genes are involved in the pathogenesis of portal hypertension. Homozygous missense mutation in DGUOK gene is found to be related with non-cirrhotic portal hypertension. On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension. The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome.

Life-threatening causes of portal hypertension include cirrhosis, severe portal venous obstruction or thrombosis (Budd-Chiari syndrome), and fulminant hepatic failure (e.g., due to hepatitis). Common causes for portal hypertension include alcoholic hepatitis, autoimmune disease, bacterial intestinal infections (e.g., recurrent E.coli infection), chronic hepatitis, cirrhosis, fatty liver, schistosomiasis, and sickle cell disease.

Portal hypertension must be differentiated from other diseases that cause ascites, splenomegaly, hematemesis or melena, bacterial peritonitis, hydrothorax, hypoxemia, and pulmonary hypertension. Diseases that must be differentiated from portal hypertension are malignant ascites, nephrogenic ascites, tuberculosis, thalassemia, sickle cell disease, hereditary spherocytosis, peptic ulcer disease, Mallory-Weiss tear, colorectal cancer, secondary bacterial peritonitis, malignant hydrothorax, sarcoidosis, nephrotic syndrome, heart failure, central nervous system depression, muscular weakness, idiopathic pulmonary hypertension, valvular heart disease, and connective tissue disease.

The incidence of portal hypertension is approximately 25,000 cases per 100,000 individuals with non-alcoholic fatty liver disease (NAFLD). The prevalence of cirrhosis, as the main cause of portal hypertension, is approximately 270 cases per 100,000 individuals in the United States. The age-adjusted mortality rate of cirrhosis is approximately 18.1 deaths per 100,000 population, based on the report of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The incidence of portal hypertension increases in early 4th decade in females and early 3rd decade in males. Cirrhosis usually affects individuals of the non-Hispanic blacks and Mexican Americans more likely. For unknown reason, portal hypertension is more prevalent among people of low socioeconomic state.

There are no established risk factors for portal hypertension. Cirrhosis as the main cause of portal hypertension has various risk factors. Common risk factors in the development of cirrhosis include intravenous drug use (IVDU), tattooing or piercing in unhygienic condition, needlestick injury, blood transfusion before 1992, viral hepatitis, and unprotected sexual intercourse.

There is insufficient evidence to recommend routine screening for portal hypertension.

Portal hypertension is increased hepatic venous pressure gradient (HVPG) above 5 mmHg. The symptoms of portal hypertension usually develop in the third and fourth decades of life, and generally start with symptoms such as esophageal varices, caput medusae, spider angioma, and splenomegaly. Esophageal varices are typically developed 5-15% per year after cirrhosis. Most of the cirrhotic patients will develop the varices during the lifetime. Approximately 60% of patients with cirrhosis develop ascites in 10 years. 10% of hospitalized patients with cirrhosis will involve in spontaneous bacterial peritonitis (SBP). If left untreated, 20-40% of patients with SBP may progress to death. The presence of variceal bleeding, spontaneous bacterial peritonitis, and hepatorenal syndrome are associated with a particularly poor prognosis among patients with portal hypertension. They are the leading causes of death among patients with portal hypertension.

Diagnostic study of choice for diagnosing portal hypertension is to measure Hepatic venous pressure gradient (HVPG). HVPG measurement is the difference between hepatic venous wedge pressure (HVWP) and free hepatic venous pressure (FHVP). HVPG reflects the intra-sinusoidal pressure. HVPG is measured through insertion of a catheter in right internal jugular vein.

The majority of patients with portal hypertension are asymptomatic. Patients with portal hypertension may have a positive history of intravenous drug use (IVDU), tattooing or piercing in unhygienic condition, needlestick injury, blood transfusion before 1992, viral hepatitis, and unprotected sexual intercourse. All of the clinical symptoms are associated with complications of the portal hypertension. Common symptoms of portal hypertension include hematemesis, melena, abdominal distention (ascites), fatigue, and loss of appetite.

Physical examination of patients with portal hypertension is usually remarkable for splenomegaly, caput medusae, and thrombocytopenia. The presence of jaundice on physical examination is highly suggestive of cirrhosis. Patients with portal hypertension usually appear ill and icteric. 

There are no diagnostic laboratory findings exclusively associated with portal hypertension. Laboratory findings related with the diagnosis of cirrhosis, as the most common underlying disease for portal hypertension, include indirect serum markers and direct fibrosis markers. Indirect serum markers are platelet count, AST/ALT index, AST/platelet ratio index, and Lok score. Direct fibrosis markers are fibrotest, fibrometer, hepascore, hyaluronic acid, and enhanced liver fibrosis.

There are no ECG findings associated with portal hypertension.

There are no x-ray findings associated with portal hypertension.

Abdominal CT scan may be helpful in the diagnosis of portal hypertension. Findings on CT scan suggestive of portal hypertension include re-canalized umbilical vein, dilated portal vein and/or splanchnic veins, esophageal varices, collaterals in any abdominal organ, splenomegaly, and ascites.

Abdominal MRI may be helpful in the diagnosis of portal hypertension. Findings on MRI suggestive of portal hypertension include re-canalized umbilical vein, dilated portal vein and/or splanchnic veins, esophageal varices, collaterals in any abdominal organ, splenomegaly, and ascites.

Echo-Doppler may be helpful in the diagnosis of portal hypertension. Findings on an echo-doppler suggestive of portal hypertension include lack of increase in portal vein diameter in response to meals, increased portal blood flow velocity, and decreased portal vein cross-sectional area. Color-Doppler ultrasound may be helpful in the diagnosis of portal hypertension. Findings on an color-doppler ultrasound suggestive of portal hypertension include increased diameter of left gastric vein, increased diameter of portal vein, and increased flow velocity in left gastric vein.

Upper endoscopy may be helpful in the diagnosis of gasteroesophageal varices. Findings on an upper endoscopy diagnostic of esophageal varices include visible submucosal tortuous veins, congested veins without compression during air insufflation, and grape-like varicose veins that may occlude the lumen. Three dimensional portal venography may be helpful in the diagnosis of gasteroesophageal varices. Findings on a portal venography diagnostic of esophageal varices include reverse flow in porto-systemic shunts, collateral veins draining into inferior vena cava (IVC), and other collateral veins.

Hepatic venous pressure gradient (HVPG) measurement is the difference between hepatic venous wedge pressure (HVWP) and free hepatic venous pressure (FHVP). HVPG reflects the intra-sinusoidal pressure. HVPG is measured through insertion of a catheter in right internal jugular vein.

Pharmacological medical therapy is recommended among patients with cirrhosis and portal hypertension which are without esophageal varices, with esophageal varices but not yet bleeding, with esophageal varices which is bleeding, and with esophageal varices which has already bled. Pharmacological medical therapies for portal hypertension include non-selective beta blockers (NSBB), analogues of nitric oxide (NO), and vasoactive agents.

Surgery is not the first-line treatment option for patients with portal hypertension. Surgery is usually reserved for patients with either severe cirrhosis, esophageal varices, splenomegaly, ascites, or liver failure.

There are no established measures for the primary prevention of portal hypertension. Effective measures for the primary prevention of liver diseases, as the main causes of portal hypertension, include hepatitis B vaccination, avoid unprotected sexual intercourse, precise screening of the blood products before infusion, reducing alcohol consumption, overweight and obesity prevention, and diabetes mellitus prevention.

There are no established measures for the secondary prevention of portal hypertension. Effective measures for the secondary prevention of liver diseases, as the main causes of portal hypertension, include treatment of hepatitis B and hepatitis C infections, alcohol abuse management, weight loss or management, and proper management of diabetes mellitus.

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

In 1511, Leonardo da Vinci, Italian Renaissance polymath, first describe the portal hypertension in an illustration in his textbook “De humanis corpore“. “… the artery and the vein which go from the spleen to the liver become so large, to block the blood coming from the mesenteric vein; the latter vein dilates and becomes tortuous like a snake, that the liver dries and become like frozen bran, in colour and consistency…”, this presentation was inaccurately described as the cause of portal hypertension. In 1937, William Thompson, a Canadian biologist, measured the portal vein pressure for the first time. He did the measurements in the open abdomen for both inferior vena cava (IVS) and portal vein. In 1939, Crafoord and Fenckner, Dutch cardiac surgeons, used sclerosing agents (quinine solutions) to treat the esophageal varices via endoscopy. The procedure was rarely used because of high rates of re-bleeding. In 1980s, researchers have observed that endoscopic sclerotherapy is more efficient than surgical shunting in preventing recurrent variceal bleeding. In 1967, Thomas Earl Starzl, an American physician, mentioned that liver transplantation is the only way to treat both portal hypertension and the underlying hepatic disease.

First explanation of the portal venous system in human body Herophilos, a Greek physician IV century B.C.

First presentation of liver vascular system anatomy Mondino de Liuzzi (Mundinus), an Italian surgeon 1319

First description of portal hypertension Leonardo da Vinci, Italian Renaissance polymath 1511

First description of portal system accurately Andreas van Wesel (Andrea Vesalio in Latin), Flemish anatomist 1543

First demonstration of the portal circulation Francis Glisson, a British physician 1650

First description of the characteristics of cirrhotic liver Giovani Battista Morgagni, an Italian anatomist 1761

First coined the name cirrhosis, from antique Greek words of “Skirros” (hard, fibrotic) and “Kirrhos” (yellowish) Renè Laennec, a French physician 1819

First introduction of the term “portal hypertension” Augustin Gilbert, a French physician 1902

First showing splenomegaly as the result of portal hypertension Archibald McIndoe, a New Zealand plastic surgeon 1928

First measured the portal vein pressure William Thompson, a Canadian biologist 1937

First used percutaneous measurement of intrasplenic pressure for diagnosis of portal hypertension Lebon, an Algerian physician 1950

• Herophilos, a Greek physician, was the first scientist to explain the portal venous system in human body in the 4th century B.C. “…nature made special veins which are dedicated to the nourishment of the intestine and they do not pass to the liver; these veins end in glandular bodies, while all the other veins are carried back to the portae…”, he mentioned.^[4]
• In 1319, Mondino de Liuzzi (Mundinus), an Italian surgeon, published the textbook named “Anhotomia” and described the anatomy of liver vascular system for the first time. The book was the most reliable textbook of anatomy for about 200 years and been partially modified by Avicenna (1000 years ago).
• In 1511, Leonardo da Vinci, Italian Renaissance polymath, first describe the portal hypertension in an illustration in his textbook “De humanis corpore“. “… the artery and the vein which go from the spleen to the liver become so large, to block the blood coming from the mesenteric vein; the latter vein dilates and becomes tortuous like a snake, that the liver dries and become like frozen bran, in colour and consistency…”, this presentation was inaccurately described as the cause of portal hypertension.^[5]
• In 1543, Andreas van Wesel (Andrea Vesalio in Latin), Flemish anatomist, described portal system accurately for the first time in his textbook called “De humani corporis fabrica”.^[6]
• In 1650, Francis Glisson, a British physician, demonstrated the portal circulation for the first time, using goat as study model.^[7]
• In 1761, Giovani Battista Morgagni, an Italian anatomist, described the characteristics of cirrhotic liver in his precious textbook named “De sedibus and causis morborum per anatomen indagatis“.^[8]
• In 1819, Renè Laennec, a French physician, coined the term cirrhosis in his textbook, from antique Greek words of “Skirros” (hard, fibrotic) and “Kirrhos” (yellowish). He also mentioned his new invention “stethoscope” in the textbook.^[6]
• In 1902, Augustin Gilbert, a French physician, described the properties of collateral circulations from portal to systemic veins and also introduced the term “portal hypertension” for the first time.^[6]
• In 1928, Archibald McIndoe, a New Zealand plastic surgeon, showed that splenomegaly is a result of portal hypertension.^[9]
• In 1937, William Thompson, a Canadian biologist, measured the portal vein pressure for the first time. He did the measurements in open abdomen for both inferior vena cava (IVS) and portal vein.^[10]
• In 1950, Lebon, an Algerian physician, used percutaneous measurement of intrasplenic pressure for diagnosis of portal hypertension for the first time.^[11]

• In 1930, Westfal, a German physician, used some endoscopic balloons to compress and treat bleeding esophageal varices.^[12]
• In 1939, Crafoord and Fenckner, Dutch cardiac surgeons, used sclerosing agents (quinine solutions) to treat the esophageal varices via endoscopy. The procedure was rarely used because of high rates of re-bleeding.^[13]

• In 1877, Nicholas Eck, a German physician, did the first portocaval shunt to treat the liver congestion in dogs.^[14]
• In 1894, Guido Banti, an Italian physician, postulated that splenectomy is an option for treatment of portal hypertension.^[15]
• In 1945, Allan Whipple, an American surgeon, reported treatment of some cases of the portal hypertension with shunts. He eventually tried shunts between different mesenteric veins. Finally, he found portocaval shunt as the best choice.

• In 1985, David Westaby, a British gastroenterologist, postulated that variceal sclerosing therapy is an better option than pharmacotherapy in the treatment of portal hypertension.^[16]
• In 1980s, researchers have observed that endoscopic sclerotherapy is more efficient than surgical shunting in preventing recurrent variceal bleeding.^[17]

• In 1967, Thomas Earl Starzl, an American physician, mentioned that liver transplantation is the only way to treat both portal hypertension and the underlying hepatic disease.^[18]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Based on the etiology, portal hypertension may be classified as pre-hepatic, intra-hepatic, and post-hepatic. Intra-hepatic portal hypertension classified into pre-sinusoidal, sinusoidal, and post-sinusoidal disorders. Based on the functional impairment in the liver, portal hypertension may be classified as cirrhotic and non-cirrhotic.

• Based on the etiology, portal hypertension may be classified as pre-hepatic, intra-hepatic, and post-hepatic.
• Intra-hepatic portal hypertension classified into pre-sinusoidal, sinusoidal, and post-sinusoidal disorders.
• Based on the functional impairment in the liver, portal hypertension may be classified as cirrhotic and non-cirrhotic.^[1]

Portal Hypertension classification

Functional

Etiology

Cirrhotic

Non-cirrhotic

Without any underlying cause

Pre-hepatic portal hypertension

Intra-hepatic portal hypertension

Post-hepatic portal hypertension

Idiopathic portal hypertension

Pre-sinusoidal disorders

Sinusoidal disorders

Post-sinusoidal disorders

Group		Wedged hepatic venous pressure (WHVP)	Free hepatic vein pressure (FHVP)	Hepatic vein pressure gradient (HVPG)	Cause
Pre-hepatic portal hypertension		Normal	Normal	Normal	Increase in portal veins resistance Inflammatory portal vein closure due to thrombosis[2]
Intra-hepatic portal hypertension[3]	Pre-sinusoidal disorders	Normal	Normal	Normal	Portal vein thrombosis Schistosomiasis Primary biliary cirrhosis
	Sinusoidal disorders	Elevated	Elevated	Elevated	Cirrhosis
	Post-sinusoidal disorders	Elevated	Normal	Elevated	Right heart failure Inferior vena cava (IVC) obstruction
Post-hepatic portal hypertension[4]		Elevated	Elevated	Normal	Increased post-hepatic vessels resistance

• Idiopathic portal hypertension (IPH) is due to obstruction and stenosis of intra-hepatic portal vasculature.^[5]
• Idiopathic portal hypertension (IPH) has 4 stages:^[5]
  1. Stage I: Non-atrophic liver without subcapsular parenchymal atrophy.
  2. Stage II: Non-atrophic liver with subcapsular parenchymal atrophy.
  3. Stage III: Atrophic liver with subcapsular parenchymal atrophy.
  4. Stage IV: Portal venous occlusive thrombosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Life-threatening causes of portal hypertension include cirrhosis, severe portal venous obstruction or thrombosis (Budd-Chiari syndrome), and fulminant hepatic failure (e.g., due to hepatitis). Common causes for portal hypertension include alcoholic hepatitis, autoimmune disease, bacterial intestinal infections (e.g., recurrent E.coli infection), chronic hepatitis, cirrhosis, fatty liver, schistosomiasis, and sickle cell disease.

• Life-threatening causes of portal hypertension include cirrhosis, severe portal venous obstruction or thrombosis (Budd-Chiari syndrome), and fulminant hepatic failure (e.g., due to hepatitis).

Portal hypertension may be caused by:^[1][2][3]

• Alcoholic hepatitis
• Autoimmune disease
• Bacterial intestinal infections
  • Recurrent E.coli infection
• Chronic hepatitis
• Cirrhosis
• Fatty liver
• Schistosomiasis
• Sickle cell disease

Less common causes of portal hypertension include:^{[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]}

• Antiretroviral therapy
• Crohn’s disease
• Turner syndrome
• Antiphospholipid syndrome
• Adams-Olivier syndrome
• Arsenicals
• Beck’s disease
• Common variable immunodeficiency syndrome
• Connective tissue diseases
• Cardiomyopathy
• Congestive heart failure
• Constrictive pericarditis
• Congenital abnormalities
• Familial cases
• Fulminant hepatic failure
• Hashimoto’s thyroiditis
• Hodgkin’s lymphoma
• Human immunodeficiency virus (HIV) infection
• Inferior vena cava obstruction
• Inherited thrombophilias
• Idiopathic tropical splenomegaly
• Myeloproliferative neoplasm
• Osteomyelosclerosis
• Partial nodular transformation
• Phosphomannose isomerase deficiency
• Portal vein occlusion
• Solid organ transplant
  • Renal transplantation
  • Liver transplantation
• Splenic vein thrombosis
• Thiopurine derivatives
  • Didanosine
  • Azathioprine
  • Cis-thioguanine
• Tricuspid insufficiency
• Umbilical sepsis
• Vitamin A
• Wilson’s disease

Portal hypertension is caused by a mutation in the following genes:^{[21][22][23][24][25][26][21][27][28][29][30]}

• Leukotriene B4 (LTB4)
• Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)
• Endothelin receptor type A (EDNRA)
• Deoxyguanosine kinase (DGUOK)
• Adenosine deaminase (ADA)
• Phospholipase A2 (PL2G10)
• Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3)
• Glutathione peroxidase 3 (GPX3)
• Prostaglandin E receptor 2 (PTGER2)
• Endothelin (EDN1)
• Natriuretic peptide receptor 3 (NPR3)
• Cluster of differentiation 44 (CD44)
• Transforming growth factor (TGF)-β
• ATP-binding cassette, subfamily C, member 1 (ABCC1)

Prehepatic causes of portal hypertension include:^[2][15][16]

• Bacterial intestinal infections
  • Recurrent E.coli infection
• Congenital abnormalities
• Idiopathic tropical splenomegaly
• Portal vein occlusion
• Solid organ transplant
  • Renal transplantation
  • Liver transplantation
• Splenic vein thrombosis
• Umbilical sepsis

Intrahepatic causes of portal hypertension include:^{[1][5][6][7][8][9][10][11][12][13][14][17][18][19][20]}

• Adams-Olivier syndrome
• Alcoholic hepatitis
• Antiretroviral therapy
• Arsenicals
• Autoimmune disease
• Beck’s disease
• Chronic hepatitis
• Cirrhosis
• Common variable immunodeficiency syndrome
• Connective tissue diseases
• Crohn’s disease
• Familial cases
• Fatty liver
• Fulminant hepatic failure
• Hashimoto’s thyroiditis
• Hodgkin’s lymphoma
• Human immunodeficiency virus (HIV) infection
• Osteomyelosclerosis
• Partial nodular transformation
• Phosphomannose isomerase deficiency
• Schistosomiasis
• Thiopurine derivatives
  • Didanosine
  • Azathioprine
  • Cis-thioguanine
• Turner syndrome
• Vitamin A
• Wilson’s disease

Posthepatic causes of portal hypertension include:^[3][4]

• Antiphospholipid syndrome
• Cardiomyopathy
• Congestive heart failure
• Constrictive pericarditis
• Inferior vena cava obstruction
• Inherited thrombophilias
• Myeloproliferative neoplasm
• Sickle cell disease
• Tricuspid insufficiency

Cardiovascular	Cardiomyopathy, Congestive heart failure, Constrictive pericarditis, Inferior vena cava obstruction, Splanchnic arteriovenous fistula, Tricuspid insufficiency.
Chemical/Poisoning	Arsenicals.
Dermatological	NISCH syndrome.
Drug Side Effect	Didanosine, Thioguanine, Vitamin A, Azathioprine, Cis-thioguanine, Antiretroviral therapy, Adams-Olivier syndrome.
Ear Nose Throat	No underlying causes
Endocrine	Hashimoto’s thyroiditis.
Environmental	Vitamin A, Alcoholic hepatitis.
Gastroenterology	Alcoholic hepatitis, Biliary atresia, Budd-Chiari syndrome, Cholestasis, Chronic hepatitis, Chronic liver disease, Cirrhosis, Congenital atresia or stenosis of portal vein, Congenital hepatic fibrosis, Congenital narrowing of the portal vein, Cruveilhier-Baumgarten syndrome, Fatty liver, Focal nodular hyperplasia, Fulminant hepatic failure, Hepatic amyloidosis with intrahepatic cholestasis, Hepatic arterioportal fistula, Hepatic portal vein obstruction, Hepatic vein occlusion, Hepatic vein thrombosis, Hepatic venoocclusive disease with immunodeficiency, Idiopathic liver cirrhosis, Idiopathic portal hypertension, Idiopathic tropical splenomegaly, Liver fibrosis, Mosse syndrome, Neonatal hepatitis, Nodular regenerative hyperplasia of the liver, Obliterative portal venopathy, Partial nodular transformation, Portal hypertension due to intrahepatic block, Portal vein abnormality, Portal vein compression, Portal vein occlusion, Portal vein thrombosis , Primary biliary cirrhosis, Primary sclerosing cholangitis, Splenic vein thrombosis, Alpha-1-antitrypsin deficiency, Progressive familial intrahepatic cholestasis, Berry aneurysm, Hepatic metastasis, Pancreatic cancer, NISCH syndrome, Crohn’s disease.
Genetic	Alpha-1-antitrypsin deficiency, COACH syndrome, Cystic fibrosis, Gaucher disease, Glycosylphosphatidylinositol deficiency, Hemochromatosis, Interferon gamma receptor 1 deficiency, NISCH syndrome, Progressive familial intrahepatic cholestasis, Wilson’s Disease , Hepatic venoocclusive disease with immunodeficiency, Turner syndrome, Leukotriene B4 (LTB4) mutation, Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) mutation, Endothelin receptor type A (EDNRA) mutation, Deoxyguanosine kinase (DGUOK) mutation, Adenosine deaminase (ADA) mutation, Phospholipase A2 (PL2G10) mutation, Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) mutation, Glutathione peroxidase 3 (GPX3) mutation, Prostaglandin E receptor 2 (PTGER2) mutation, Endothelin (EDN1) mutation, Natriuretic peptide receptor 3 (NPR3) mutation, Cluster of differentiation 44 (CD44) mutation, Transforming growth factor (TGF)-β mutation, ATP-binding cassette, subfamily C, member 1 (ABCC1) mutation, Phosphomannose isomerase deficiency
Hematologic	Blackfan Diamond anemia, Congenital pure red cell aplasia , Myeloproliferative diseases, Mosse syndrome, Hemochromatosis, Osteomyelosclerosis, Hodgkin’s lymphoma, Sickle cell disease, Inherited thrombophilias, Antiphospholipid syndrome, Human immunodeficiency virus (HIV) infection, Myeloproliferative neoplasm, Common variable immunodeficiency syndrome.
Iatrogenic	Solid organ transplant, Renal transplantation, Liver transplantation.
Infectious Disease	Schistosomiasis , Umbilical sepsis, Viral hepatitis, Recurrent E.coli infection.
Musculoskeletal / Ortho	Osteomyelosclerosis, Connective tissue diseases.
Neurologic	Berry aneurysm, Cerebral calcification, Beck’s disease.
Nutritional / Metabolic	Gaucher disease, Glycosylphosphatidylinositol deficiency, Wilson’s disease, Vitamin A, Alcoholic hepatitis.
Obstetric/Gynecologic	Antiphospholipid syndrome.
Oncologic	Extrinsic compression (tumors), Hepatic metastasis, Hodgkin’s lymphoma, Pancreatic cancer.
Opthalmologic	No underlying causes
Overdose / Toxicity	Didanosine, Thioguanine.
Psychiatric	No underlying causes
Pulmonary	Cystic fibrosis, Alpha-1-antitrypsin deficiency, Berry aneurysm, Cirrhosis, Pulmonary emphysema, Cerebral calcification.
Renal / Electrolyte	Polycystic kidney disease.
Rheum / Immune / Allergy	Hepatic venoocclusive disease with immunodeficiency, Granulomatous diseases (Sarcoidosis, Tuberculosis), Hashimoto’s thyroiditis.
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Granulomatous diseases (Sarcoidosis, Tuberculosis), Extrinsic compression (tumors), Inferior vena cava obstruction.

Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Portal hypertension must be differentiated from other diseases that cause ascites, splenomegaly, hematemesis or melena, bacterial peritonitis, hydrothorax, hypoxemia, and pulmonary hypertension. Diseases that must be differentiated from portal hypertension are malignant ascites, nephrogenic ascites, tuberculosis, thalassemia, sickle cell disease, hereditary spherocytosis, peptic ulcer disease, Mallory-Weiss tear, colorectal cancer, secondary bacterial peritonitis, malignant hydrothorax, sarcoidosis, nephrotic syndrome, heart failure, central nervous system depression, muscular weakness, idiopathic pulmonary hypertension, valvular heart disease, and connective tissue disease.

• Portal hypertension must be differentiated from other diseases that cause ascites, splenomegaly, hematemesis or melena, bacterial peritonitis, hydrothorax, hypoxemia, and pulmonary hypertension.
• Portal hypertension must be differentiated from various diseases as in the following table.^{[1][2][3][4][5][6][7][8][9][10][11]}

Differentiating symptom	Diseases	Laboratory Findings							Physical Examination						History and Symptoms				Other Findings
		CBC	ESR	Alb	Iron	Ascites fluid	PBS	Cr	Abdominal tenderness	Pale conjunctiva	Fever	Pitting edema	Apnea/ Baradypnea	Murmur	Weight loss	Weakness	Cough	Dyspnea
	Portal Hypertension	–	–	–	–	Transudate	–	↑	+	–	–	–	–	–	–	–	–	–	Cirrhosis
Ascites	Malignant ascites	–	↑↑	↓	–	Exudate	–	–	–	–	–	–	+/-	–	+	+	–	–	Jaundice
	Nephrogenic ascites	–	–	↓↓	↓	Exudate	–	↑↑	–	+	–	++	+	–	–	+	–	–	↑K, Na
	Tuberculosis	↑lymph.	↑	↓	–	Exudate	–	–	–	–	+	–	+	–	+	+	++	+	Sweating
Splenomegaly	Thalassemia	↓MCV ↓HGB	–	–	↓	–	Microcytic anemia	–	–	+	–	–	–	–	–	+	–	–	↑HGB-A2
	Sickle cell disease	↓HGB	–	–	↓	–	Sickle RBC	–	+	+	+	–	–	–	–	+	–	+	Bone pain
	Hereditary spherocytosis	↓MCV ↓HGB	–	–	↓	–	Spherocyte	–	–	+	–	–	–	–	+	+	–	–	Osmotic fragility test
Hematemesis/ Melena	Peptic ulcer disease	↓HGB	–	–	↓	–	–	–	+	+	–	–	–	–	+	+	–	–	Dyspepsia
	Mallory-Weiss tear	–	–	–	–	–	–	–	+	–	–	–	–	–	–	–	–	–	Hx of vomiting
	Colorectal cancer	↓HGB	↑↑	↓	↓↓	–	–	–	–	+	–	–	–	–	+	+	–	–	Changing bowel habit
Bacterial peritonitis	Secondary bacterial peritonitis	↑Neut.	↑	–	–	Exudate	–	–	++	+	+++	–	+	–	–	+	–	–	Guarding
Hydrothorax	Malignancy	↑↑WBC	↑↑	↓↓	–	–	–	–	–	+	–	–	+	–	+	+	+	+	Chest pain
	Sarcoidosis	↑WBC	↑↑	–	–	–	–	↑	–	+	–	–	+	–	+	+	+	+	Bilateral hilar adenopathy
	Nephrotic syndrome	–	↑	↓↓	↓	–	–	↑↑	–	+	–	++	–	–	–	+	–	–	↑K, Na
Hypoxemia	Heart failure	–	–	–	–	–	–	–	–	–	–	++	–	+	+	+	+	+	EF < 40%
	Central nervous system depression	–	–	–	–	–	–	–	–	–	–	–	+	–	–	–	–	+	Opioid overdose
	Muscular weakness	–	–	–	–	–	–	–	–	–	–	–	–	–	+	++	–	–	Neuromuscular disease
Pulmonary hypertension	Idiopathic pulmonary arterial hypertension	–	↑	–	–	–	–	–	–	–	–	–	–	–	+	+	+	+	Hemoptysis
	Valvular heart disease	–	–	–	–	–	–	–	–	–	–	–	–	++	–	+	–	–	Dyspnea on exertion
	Connective tissue diseases	–	↑	–	–	–	–	↑	–	–	–	–	–	+	–	+	–	–	Aortic dissection

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The incidence of portal hypertension is approximately 25,000 cases per 100,000 individuals with non-alcoholic fatty liver disease (NAFLD). The prevalence of cirrhosis, as the main cause of portal hypertension, is approximately 270 cases per 100,000 individuals in the United States. The age-adjusted mortality rate of cirrhosis is approximately 18.1 deaths per 100,000 population, based on the report of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The incidence of portal hypertension increases in early 4th decade in females and early 3rd decade in males. Cirrhosis usually affects individuals of the non-Hispanic blacks and Mexican Americans more likely. For unknown reason, portal hypertension is more prevalent among people of low socioeconomic state.

• The incidence of portal hypertension is approximately 25,000 cases per 100,000 individuals with non-alcoholic fatty liver disease (NAFLD).^[1]
• The incidence of non-cirrhotic portal hypertension is approximately 15,000 cases per 100,000 individuals with portal hypertension.^[2]
• The incidence of idiopathic portal hypertension is approximately 23,000 cases per 100,000 individuals with portal hypertension.^[3]
• In western countries, the incidence of idiopathic portal hypertension is approximately 2,000-3,000 cases per 100,000 individuals with portal hypertension.^[4]
• The incidence of idiopathic portal hypertension is approximately 14,000-27,000 cases per 100,000 individuals with non-cirrhotic portal hypertension.^[5]

• The prevalence of cirrhosis, as the main cause of portal hypertension, is approximately 270 cases per 100,000 individuals in the United States.^[6]

• The age-adjusted mortality rate of cirrhosis is approximately 18.1 deaths per 100,000 population, based on the report of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).^[7]
• Mortality rates for white males, black males, white females, and black females declined by 43.2, 70.1, 40.2, and 76.5 percent, respectively.^[7]

• The incidence of portal hypertension increases in early 4th decade in females and early 3rd decade in males.^[2]
• Idiopathic portal hypertension commonly affects individuals between 43-56 years old.^[8]
• Non-cirrhotic portal hypertension commonly affects individuals between 25-35 years old.^[8]

• Cirrhosis usually affects individuals of the non-Hispanic blacks and Mexican Americans more likely.^[6]
• Mortality rates for white males, black males, white females, and black females declined by 43.2, 70.1, 40.2, and 76.5 percent, respectively.^[7]

• Males are more commonly affected by idiopathic portal hypertension than females. The male to female ratio is approximately 2 to 1.^[8]
• Females are more commonly affected by non-cirrhotic portal hypertension than males. The female to male ratio is approximately 3 to 1.^[8]

• For unknown reason, portal hypertension is more prevalent among people of low socioeconomic state.^[9]
• The prevalence of the portal hypertension is decreased over the years in Japan, maybe because of hygiene and health improvement.^[10]

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